Hematopoietic cells are highly sensitive to radiation damage and their loss after radiation exposure results in both neutropenia and thrombocytopenia. Severe neutropenia results in sepsis and death due to opportunistic infections and thrombocytopenia results in increased risk of hemorrhage and death due to bleeding. Development of treatment that substantially improves thrombocytopenia after radiation exposure would be a significant advance. The aim of this project is to study a very promising new drug, pegylated thrombopoietin mimetic peptide (Peg-TPO-mp) that will likely significantly improve platelet recovery after high dose total body irradiation (TBI) in the well established dog model. Peg-TPO-mp will initially be administered as a single agent drug beginning at 24 hours after TBI dose of 6 to 8 Gy. Supportive care administered to dogs will include empiric broad spectrum antibiotics and transfusions with irradiated blood products transfusions. Next, Peg-TPO-mp will be administered in combination with granulocyte colony stimulating factor (G-CSF), fms-like tyrosine kinase-3 ligand (Flt3 ligand [FL]) and keratinocyte growth factor (KGF) after lethal dose TBI. The aim is to study if Peg-TPO- mp has synergistic activity with these cytokines to improve survival and mitigate the duration and severity of thrombocytopenia. We will study Peg-TPO-mp in the dog since (1) the dog model of radiation exposure and hematopoietic recovery has been highly predictive of human clinical outcomes, (2) there are extensive preliminary data with cytokines for platelet and neutrophil recovery in the dog after acute irradiation, (3) all of the human cytokines we have proposed have established biologic activity in the dog, and (4) the cytokines have been studied in humans and are in advanced stages of clinical development. The study goal is to achieve survival of dogs after an otherwise lethal dose of irradiation with a significantly reduced period of thrombocytopenia without requiring hematopoietic stem cell transplantation. [unreadable] [unreadable] [unreadable] [unreadable]